Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Spark Therapeutics, Inc, Philadelphia, Pennsylvania.
J Clin Endocrinol Metab. 2020 May 1;105(5):1302-15. doi: 10.1210/clinem/dgaa056.
Normal vitamin D homeostasis is necessary to ensure optimal mineral metabolism. Dietary insufficiency of vitamin D and the lack of sunlight each have well understood roles in vitamin D deficiency; however, the extent to which common genetic variations in vitamin D metabolizing enzymes contribute to alterations in vitamin D homeostasis remains uncertain.
To examine the possibility that common coding variation in vitamin D metabolizing enzymes alters vitamin D homeostasis we determined the effect of 44 nonsynonymous polymorphisms in CYP2R1, the vitamin D 25-hydroxylase, on enzyme function.
Twenty-one of these polymorphisms decreased activity, while 2 variants increased activity. The frequency of CYP2R1 alleles with decreased 25-hydroxylase activity is 3 in every 1000 Caucasians and 7 in every 1000 African Americans. In populations where exposure to sunlight is high, alleles with decreased function occur at a frequency as high as 8%. The pattern of selected variation as compared to nonselected variation is consistent with it being the result of positive selection for nonfunctional alleles closer to the equator. To examine this possibility, we examined the variation pattern in another protein in the vitamin D pathway, the vitamin D binding protein (GC protein). The pattern of selected variation in the GC protein as compared to nonselected variation is also consistent with it being the result of positive selection for nonfunctional alleles closer to the equator.
CYP2R1 polymorphisms have important effects on vitamin D homeostasis, and the geographic variability of CYP2R1 alleles represents an adaptation to differential exposures to UVB irradiation from sunlight.
正常的维生素 D 体内平衡对于确保最佳矿物质代谢是必要的。饮食中维生素 D 不足和缺乏阳光各自在维生素 D 缺乏中具有明确的作用；然而，维生素 D 代谢酶的常见遗传变异在多大程度上导致维生素 D 体内平衡的改变仍不确定。
为了研究维生素 D 代谢酶的常见编码变异是否改变维生素 D 体内平衡，我们确定了 CYP2R1（维生素 D 25-羟化酶）中的 44 个非同义多态性对酶功能的影响。
其中 21 个多态性降低了活性，而 2 个变体增加了活性。在每 1000 名白种人中，有 3 个等位基因的 CYP2R1 减少了 25-羟化酶的活性，而在每 1000 名非裔美国人中，有 7 个等位基因的 CYP2R1 减少了 25-羟化酶的活性。在阳光照射较高的人群中，功能降低的等位基因频率高达 8%。与非选择变异相比，选择变异的模式与其说是由于接近赤道的非功能等位基因的正选择，不如说是如此。为了研究这种可能性，我们检查了维生素 D 途径中的另一种蛋白质，即维生素 D 结合蛋白（GC 蛋白）中的变异模式。与非选择变异相比，GC 蛋白中选择变异的模式也与接近赤道的非功能等位基因的正选择结果一致。
CYP2R1 多态性对维生素 D 体内平衡有重要影响，CYP2R1 等位基因的地理变异性代表了对来自阳光的 UVB 照射的差异暴露的适应。
